ReviewBladder cancer, a two phased disease?
Section snippets
Urothelial cell carcinoma
Urothelial cell carcinomas (UCC) originate from the epithelial cells of the inner lining of the bladder wall. Seventy percent of the tumors are papillary and confined to the urothelial mucosa (stage Ta) or to the lamina propria (stage T1), whereas the remaining invade the muscle (T2), perivesical fat (T3) or surrounding organs (T4) (Fig. 1). It is not uncommon for patients with Ta/T1 tumors to show multiple, synchronous tumors. Most Ta tumors are of low grade (G1 or G2), rarely progress, and
Intraepithelial migration, intraluminal seeding, and field cancerization
Two major hypotheses have been proposed to explain the origin of synchronous and metachronous tumors in patients with UCC (Fig. 2). One assumes a monoclonal origin either through intraepithelial migration of tumor cells or by intraluminal seeding from a primary carcinoma. The second, the field cancerization model, proposes a field change and that individual cells in these fields are transformed to overt tumors and states, in the stronger version, that independent genetic events will produce
Premalignant lesions and normal urothelium show genetic changes found in cancer cells
There is growing evidence for the presence of chromosomal and genetic changes characteristic of UCC already in premalignant lesions. Hartmann et al. [6] showed that 10 out of 14 hyperplasias showed monosomies or partial loss of chromosome 9. In seven out of eight patients with genetic alterations in the hyperplasias the genetic changes were also present in the concomitant papillary tumors. In two out of six investigated patients chromosome 9 deletions were also detected in biopsies of normal
Recurrences, multifocal tumors, and the question of clonality
To investigate the possible multiclonality among multiple tumors from the same patient Sidransky et al. [19] analyzed 13 tumors from four different patients by chromosome X-inactivation analysis. In each case the tumors showed X-inactivating patterns consistent with a monoclonal origin. Li et al. [20] studied 10 patients with both synchronous and metachronous Ta/T1 tumors by X-chromosome inactivation analyses. Tumors from the same patient showed the same X-inactivation pattern indicating a
Histologic-genetic mapping
Using X chromosome inactivation analysis of cells microdissected from histological slides from a normal female human bladder, Tsai et al. [27] showed that the normal urothelium was organized in patches of monoclonal segments. These patches were about 120 mm2 and estimated to contain approximately 2 × 106 cells. Tsai et al. suggested that the patches were composed of descendants of an original founder cell, a stem cell, and estimated the number of such cells to 200–300 per bladder. This suggests
The chronology of tumor presentation does not parallel the genetic evolution
van Tilborg et al. [31] studied 11 patients with five or more recurrences using LOH and mutation analyses. For each patient tumor progression trees were constructed based on the accumulating number and sizes of the genetic changes, creating a chronology of the recurrences based on genetic events. By comparing the genetic chronology with the chronology of tumor appearance it was found that the genetic progression trees better reflected the tumor evolution than their chronologic order of
Two phases of bladder cancer
The data favoring the presence of genetic changes characteristic of frank carcinomas in morphologically normal urothelium, including LOH, chromosomal changes, and gene mutations, is more than convincing. The use of microdissection has successfully showed that premalignant lesions, hyperplasias, papillary hyperplasias, and dysplasias, adjacent to tumors show genetic aberrations similar to those in overt tumors. The detailed histologic-genetic mapping shows that regions with shared genetic
Consequences for treatment
The concept of expanded fields of preneoplastic cells that may function as a potent source for initiation of new tumor foci has important clinical consequences. One of the key challenges in the management of UCC is the high frequency of recurrences. Some success in prolonging the recurrence-free period after transurethral resection (TUR) have been accomplished by combining TUR with intravesical chemo- or immunotherapy. It is conceivable that the selective action of many chemotherapeutic agents
Acknowledgements
This work was supported by Swedish Cancer Society, the Swedish Research Council, the Petrus and Augusta Hedlunds foundation, Gunnar, Arvid and Elisabeth Nilsson foundation, and the Crafoord foundation. The author thanks Dr. Wiking Månsson at the Department of Urology, Lund University Hospital, for critically reading the manuscript.
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Cited by (28)
The Lund Molecular Taxonomy Applied to Non–Muscle-Invasive Urothelial Carcinoma
2022, Journal of Molecular DiagnosticsCitation Excerpt :Recurring tumors differ from preceding tumors with respect to genomic alterations and gene mutations.32 In particular, most recurring tumors do not originate from previous overt tumors, but rather represent clonally related de novo tumors, originating from a shared field of genomically destabilized urothelium.32,33 It could thus be more important to characterize the nature of this field (eg, the degree of field heterogeneity)34–36 to estimate risk for progression.
CIS is a surrogate marker of genetic instability and field carcinogenesis in the urothelial mucosa
2011, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :We may assume that CIS is a surrogate marker of urothelium genetic instability and field carcinogenesis. Höglund and colleagues [20], proposed the field-first-tumor-later model, in which nonmalignant but genetically modified cells spread through the epithelium and eventually develop into overt tumors independently, as our results may suggest. According to the European Organization for Research and Treatment of Cancer (EORTC) bladder cancer risk groups, patients with a non-muscle-invasive tumor with a concomitant CIS lesion have a high risk of progression and recurrence [4].
Detection of circulating tumor cells in bladder cancer patients
2009, Cancer Treatment ReviewsCitation Excerpt :Future optimization of this test could possibly justify its clinical relevance. The controversies in PCR-based protocols for CBC detection are attributed either to lack of methodological uniformity between research groups comprising specimen collection and sample handling, nucleic acid extraction methods, reaction conditions for the RT-PCR, and molecular marker selections, or they may be caused by the complex cancer biology.115 Clinical and experimental evidences suggest that the development of a single metastatic focus requires the presence of 5–10 tumor cells/ml blood.116
Molecular Pathology of the Genitourinary Tract: Prostate and Bladder
2008, Surgical Pathology ClinicsCitation Excerpt :Morphologically normal-appearing epithelium may contain few aberrations, but the number of genetic changes increases as tumorigenesis progresses, eventually reaching a state of criticality producing frank neoplasms. This process results in the heterogeneity of chromosomal abnormalities seen in the literature.175–180 One consistent pattern prevalent in urothelial carcinomas is deletion of one or both arms of chromosome 9.